Dietary antioxidants alleviate antibiotic-induced mitochondrial dysfunction through protein kinase AMP-activated alpha (AMPKα) and nuclear factor, erythroid 2 like 2 (NRF2) pathway interaction.

IF 7.7 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2025-09-16 DOI:10.1111/bph.70191

Jingyan Zhao, Bing Shang, Sha Xu, Danfeng Zheng, Xiaofang Zhang, Jiawen Lv, Yaqiong Dong, Xiaoda Yang

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引用次数: 0

Abstract

Background and purpose: Antibiotics and ibuprofen combinations cause mitochondrial toxicity and hepatotoxicity. This study investigated whether dietary antioxidants could protect against this damage via protein kinase AMP-activated alpha (AMPKα)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways.

Experimental approach: Human umbilical vein endothelial cells (HUVECs) were treated with antibiotics (kanamycin, azithromycin, ampicillin or ciprofloxacin) plus ibuprofen with or without antioxidants. Azithromycin/ibuprofen induced hepatotoxicity was evaluated in C57BL/6J mice. Mitochondrial parameters including morphology, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ_m) and key proteins (mitofusin 2, AMPKα, glycogen synthase kinase 3 beta [GSK3B], NRF2 and haem oxygenase 1 [HO1]) were analysed.

Key results: Antibiotics/ibuprofen combinations triggered mitochondrial fission, ROS overproduction and mitofusin 2 down-regulation. Four antioxidants, that is, coniferaldehyde, raspberry ketone, gastrodin and eugenol, restored mitochondrial function and morphology. Coniferaldehyde and raspberry ketone effectively prevented in vivo hepatotoxicity and inflammation. Moreover, coniferaldehyde/raspberry ketone activated NRF2/HO1 while restoring AMPKα/GSK3B signalling.

Conclusions and implications: Coniferaldehyde and raspberry ketone showed potent rescue effects in vitro against all antibiotic models and in vivo against azithromycin/ibuprofen-induced hepatotoxicity through AMPKα-GSK3B/NRF2-HO1 modulation, with favourable safety profiles.

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膳食抗氧化剂通过蛋白激酶amp活化α (AMPKα)和核因子，红细胞2样2 （NRF2）途径相互作用减轻抗生素诱导的线粒体功能障碍。

背景与目的：抗生素与布洛芬联用可引起线粒体毒性和肝毒性。本研究探讨了膳食抗氧化剂是否可以通过蛋白激酶amp活化α (AMPKα)/核因子红系2相关因子2 （NRF2）途径预防这种损伤。实验方法：用抗生素（卡那霉素、阿奇霉素、氨苄西林或环丙沙星）加布洛芬治疗人脐静脉内皮细胞（HUVECs），含或不含抗氧化剂。观察阿奇霉素/布洛芬对C57BL/6J小鼠肝毒性的影响。分析线粒体形态学、活性氧（ROS）、线粒体膜电位（ΔΨm）和关键蛋白（mitofusin 2、AMPKα、糖原合成酶激酶3 β [GSK3B]、NRF2和血红素加氧酶1 [HO1]）等参数。关键结果：抗生素/布洛芬联用引发线粒体分裂、ROS过量产生和mitofusin 2下调。松柏醛、覆盆子酮、天麻素和丁香酚四种抗氧化剂可恢复线粒体功能和形态。松柏醛和覆盆子酮能有效预防体内肝毒性和炎症。此外，松柏醛/覆盆子酮激活NRF2/HO1，同时恢复AMPKα/GSK3B信号。结论和意义：松柏醛和覆盆子酮在体外对所有抗生素模型均有有效的拯救作用，在体内通过AMPKα-GSK3B/NRF2-HO1调节对阿奇霉素/布洛芬诱导的肝毒性具有良好的安全性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.